Diabetes mellitus (commonly referred to as “diabetes”) is a syndrome of disordered metabolism resulting in abnormally high blood sugar levels. Type 2 diabetes mellitus (non-insulin dependent diabetes mellitus) is the most common form of diabetes and affects 17 million people in the U.S. Late diagnosis, coupled with poor disease management, can result in long-term complications such as microvascular damage and diseases of the eye, nervous system, and kidney. These complications lead to cataracts and blindness, nerve damage (neuropathy), kidney failure, cardiovascular disease, and death.
The Diabetes Control and Complications trial demonstrated over 5 years of follow-up study that tight control of blood glucose is effective in reducing clinical complications significantly. However, trial data showed that even optimal control of blood glucose could not prevent complications of the disease.
It is known that oxidative stress is causally related to the progression of diabetes and sequelae, co-morbidities, and complications of the disease. Oxidative stress is defined in general as excess formation and/or insufficient removal of highly reactive inflammatory species such as reactive oxygen species (ROS; including, by way of example, superoxide radical anion, hydroxyl radical, peroxyl radicals, hydroperoxyl radicals, hydrogen peroxide, and hypochlorous acid) and reactive nitrogen species (RNS; including, by way of example, nitric oxide, nitrogen dioxide, peroxynitrite, nitrous oxide, and alkyl peroxynitrates). Both ROS and RNS are generated under physiological conditions; many of these species have physiological activity as signaling molecules and defense mechanisms. However, excess generation of these reactive species, particularly when the excess continues over time, causes damage to proteins, lipids, and DNA.
Direct evidence of oxidative stress in diabetes is based on studies in which markers of oxidative stress, such as plasma and urinary F2-isoprostane, plasma and tissue levels of nitrotyrosine and superoxide radical anion, and imbalances in physiological anti-oxidants, were measured. In diabetes, these markers are generated via non-enzymatic, enzymatic and mitochondrial pathways.
Since anti-oxidants are known to abrogate oxidative stress, a number of clinical trials have evaluated the beneficial effects of anti-oxidants such as vitamin C, vitamin E, and α-lipoic acid on the course of diabetes, its sequelae, and co-morbidities. To date, only the results from clinical studies with α-lipoic acid have supported its clinical use as a treatment for diabetes and its co-morbidities. For example, in the Alpha Lipoic Acid in Diabetic Neuropathy (ALADIN) study, administration of α-lipoic acid (>600 mg/day) significantly improved patient symptoms. The ALADIN II Study demonstrated that long-term (24 months) use of α-lipoic acid (600 or 1200 mg daily) improved nerve function. ALADIN III, a randomized multicenter double-blind placebo controlled study, showed that in a cohort of 509 patients, 600 mg α-lipoic acid administered daily for 6 months improved neuropathy impairment score as early as 19 days, which was maintained up to 7 months. The DEKAN (Deutsche kardiale autonome neurpathie) study evaluated the effect of 800 mg α-lipoic acid or placebo daily in diabetic patients with cardiac autonomic neuropathy for 4 months and showed that heart rate variability, an indicator of cardiac autonomic neuropathy, significantly improved with α-lipoic acid treatment. The SYDNEY trial investigated the effect of α-lipoic acid treatment on sensory symptoms of diabetic polyneuropathy as assessed by the Total Symptom Score. Administration of α-lipoic acid over a 3-week period improved sensory symptoms such as pain, prickling, and numbness. A recent meta-analysis of clinical trials with α-lipoic acid concluded that treatment with α-lipoic acid (600 mg/day) over a 3-week period is safe and effective in improving positive neuropathic symptoms as well as neuropathic deficits. [J. S. Johansen, A. K. Harris, D. J. Rychly, and A. Ergul, “Oxidative stress and the use of antioxidants in diabetes: Linking basic science to clinical practice,” Cardiovasc Diabetol 2005; 4:5, and references therein]
α-Lipoic acid is the common name for the chiral compound 1,2-dithiocyclopentane-3-valeric acid. α-Lipoic acid is available commercially as both the racemic mixture, RS-α-lipoic acid (also commonly known as thioctic acid), and as the single enantiomer, R-(+)-α-lipoic acid. All of the clinical studies presented above used RS-α-lipoic acid.
R-(+)-α-lipoic acid is the form of α-lipoic acid found in the body. Lysine-bound R-(+)-α-lipoate is a coenzyme of α-ketoacid dehydrogenases (pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, etc.) and acts at a key site in the sugar and energy metabolism of the cell. In addition, R-(+)-α-lipoate functions as a physiological redox system and is reduced intracellularly to its corresponding R-(+)-α-dihydrolipoate, which is subsequently re-oxidized, both intra- and extra-cellularly, to R-(+)-α-lipoate. Dihydrolipoate is able to regenerate other anti-oxidants such as vitamin C, vitamin E, and reduced glutathione through redox cycling.
It is well known that the pharmacological properties of the two enantiomers of α-lipoic acid differ with respect to their physiological activities. By way of example, U.S. Pat. Nos. 5,693,664, 5,948,810, 6,284,787, and U.S. Patent Application Publication No. US 2008/0095741 (all to Wessel et al.) disclose that R-(+)-α-lipoic acid, its water-soluble salts, its esters, and its amides are more suitable for the prevention and treatment of diabetes and its complications than are the enantiomeric S-(−)-α-lipoic acid, its water-soluble salts, its esters, and its amides. (The water-soluble salts disclosed by Wessel include salts of organic amines, such as α-methylbenzylamine, diphenylamine, trometamol, and 2-amino-2-hydroxymethyl-1,3-propylene glycol.) For example, glucose assimilation was stimulated by the R-enantiomer of lipoic acid by a factor greater than 2, comparable to the effect of 200 nM insulin, whereas the S-enantiomer effected little or no change. Likewise, R-(+)-α-lipoate stimulated the translocation of glucose transporters (GLUT 1 and GLUT 4) from the cytosol to the plasma membrane; S-(−)-α-lipoate had no effect or has an inhibiting effect and appeared to lower the total content of glucose transporters. Further, the activity of a key enzyme involved in glucose metabolism, pyruvate dehydrogenase, was increased by R-(+)-α-lipoate but inhibited by S-(−)-α-lipoate.
It is also known that RS-α-lipoic acid is more stable than R-(+)-α-lipoic acid. RS-α-Lipoic acid may be stored in a closed and sealed amber container at room temperature for a year or longer. In contrast, R-(+)-α-lipoic acid must be stored in a closed and sealed amber container at refrigerated temperatures and must be used within a few months, since it gradually polymerizes to intractable polymers and degrades to physiologically and therapeutically inactive compounds by loss of sulfur-containing compounds.
Further, it is known that adequate magnesium is essential for glycolysis, formation of adenosine-3″,5″-cyclic monophosphate, energy-dependent membrane transport, and over 300 other enzyme processes. Magnesium plays the role of a second messenger for insulin action. Conditions associated with insulin resistance (i.e., reduced sensitivity to the activity of insulin), such as diabetes, hypertension or aging, are also associated with low intracellular magnesium contents. In diabetes mellitus, low intracellular magnesium levels have been reported, likely as a result from both increased urinary losses and insulin resistance. Chronic magnesium supplementation can contribute to an improvement in both islet beta-cell response and insulin action in non-insulin-dependent diabetic subjects.
Therefore, a significant, unmet need exists for provision of a stable drug for preventing or treating diabetes mellitus and sequelae, complications, and co-morbidities. If that stable drug contained magnesium, the properties of magnesium disclosed above indicate that the stable, magnesium-containing drug would provide additive therapeutic benefits to those suffering from metabolic disorders related to disordered glycolysis. The present invention addresses this unmet need by providing a stable magnesium-containing drug.